The purpose of the K23 research study is to define the mechanisms by which increased levels of insulin affect brain regions involved in food reward-motivation and influence eating behavior. This study will provide critical data necessary for the investigation of novel treatments that target attenuating the effects of hyperinsulinemia on the brain, in order to curb food cravings and excess energy intake, thereby diminishing weight gain. The specific aims of this research project are to investigate the effect of insulin on neural responses to food cues and eating-behaviors in overweight/obese and lean individuals and to assess the influence insulin resistance has on these neural mechanisms and food intake. The study is a cross-sectional, experimental study assessing neural responses in reward-motivation, decision-making, and homeostatic brain regions in response to acute, peripheral administration of insulin. While undergoing hyperinsulinemic-euglycemic clamp vs. saline-euglycemic control, functional magnetic resonance imaging (fMRI) scans will be conducted to assess neural responses in 30 overweight/obese and 20 lean individuals during viewing of high-calorie food pictures. Each of the 50 subjects will undergo hyperinsulinemic-euglycemic- and saline-euglycemic- fMRI procedures in randomized fashion on two separate days. Food craving and hunger will be assessed throughout the experiment and food intake will be measured following both the hyperinsulinemic-euglycemic- and saline- euglycemic- fMRI procedures. The role of insulin resistance on the observed neural responses and on eating behavior will also be investigated. Results obtained from this study will provide insight into how insulin affects neural mechanisms and eating behaviors in obese and lean individuals and help determine the role insulin resistance may play in these mechanisms. This study will contribute to the understanding of pathophysiologic mechanisms involved in obesity and has the potential to impact interventions for obesity and type 2 diabetes by elucidating therapeutic targets to attenuate food craving and intake of high-calorie foods. Additionally, the proposed project and vital behavioral-neuroscience training will provide the candidate with the data and knowledge required for a successful R01 application. The goals of this proposal are consistent with the Strategic Plan for NIH Obesity Research to discover fundamental biological processes that regulate body weight and influence behavior and to understand the factors that contribute to obesity and its consequences. Elucidating how insulin affects neural mechanisms and eating behaviors in obese individuals and determining the role insulin resistance and hyperinsulinemia may play in these mechanisms will significantly contribute to understanding pathophysiologic mechanisms involved in obesity and high-calorie food consumption, as well as potentially impact therapeutic interventions for obesity and type 2 diabetes.